Traumatic brain injury (TBI) is a significant health problem in the United States.  The Centers for Disease Control and Prevention (CDC) estimates that 1.7 million people sustain traumatic brain injury in the United States each year;  52,000 die; 275,000 are hospitalized; and 1.4 million, nearly 80%, are treated and released from an emergency [...]

Conventional drug discovery strategies have had very little success at finding small molecules that can potently disrupt protein-protein interactions which underlie the assembly or regulation of large, multi-protein complexes.  This is because the interaction surfaces are large, frequently flat, and therefore lack binding elements for small molecules that can effectively inhibit binding of a protein [...]

Why make allosteric modulators of PDE4?  There are four PDE4 genes in mammals (PDE4A-B) and each gene encodes multiple transcripts.  PDE4 splice isoforms are grouped as “long”, “short” and “super-short” based on their N-terminal sequence.  All splice isoforms contain the UCR2 regulatory domain as shown in the cartoon.

Previous efforts to develop drug targeting [...]